Trematocidal Synthetic Perioxides

杀吸虫合成过氧化物

• 批准号: 7648067
• 负责人: Jonathan L Vennerstrom
• 金额: $ 15.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648067
• 关键词: Acids; Acute; Adamantane; Address; Adolescent; Adult; Affect; Bile fluid; Biological Assay; Carboxylic Acids; Cells; Characteristics; Chemicals; Chronic; Clonorchis sinensis; Country; Cyclohexanes; Data; Disease; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Ensure; Enzymes; Fasciola hepatica; Fascioliasis; Feedback; Goals; Hepatic; Hepatica; Human; In Vitro; Infection; Inhibitory Concentration 50; Investigation; Lead; Libraries; Liver diseases; Measures; Metabolic; Metabolism; Modeling; Molecular Target; Morbidity - disease rate; Muscle; Myoblasts; Oral; Parasites; Peroxides; Pharmaceutical Preparations; Plant Roots; Plasmodium falciparum; Praziquantel; Prevention; Prodrugs; Property; Protein Isoforms; Rattus; Resistance development; Rural; Screening procedure; Skeletal Muscle; Staging; Surface; Testing; Toxic effect; Treatment Efficacy; Vaccines; analog; base; cytotoxicity; design; disorder prevention; drug development; flexibility; foodborne; functional group; in vitro testing; in vivo; insight; novel; process optimization; public health relevance; research study; triclabendazole

DESCRIPTION (provided by applicant): Food-borne trematodiases affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of food-borne tremotodiases, effective drugs are the only practical means of morbidity control. Importantly, new drugs for these diseases are urgently needed as praziquantel and triclabendazole are the only drugs available and the development of resistance cannot be ignored, particularly in view of the large- scale use of praziquantel in many endemic countries. At the root of this project is our discovery that several synthetic peroxides also possess strong trematocidal activity. We propose to further explore the potential of synthetic peroxides as novel trematocidal drugs. The identification of a new, broad-spectrum, orally-active synthetic peroxide trematocidal drug development candidate will minimize drug-resistance and lead to superior treatment and control options for food-borne trematodiases. Essential characteristics of a new drug development candidate include an economically-feasible and scalable synthesis, excellent oral activity, low potential for toxicity and resistance development, broad spectrum of trematocidal activity, and high efficacy against all parasite stages in the vertebrate host. More specifically, our objective is to identify a drug development candidate with 100% worm burden reductions against juvenile and adult F. hepatica and C. sinensis at doses of < 100 mg/kg and with an excellent ADME profile (predicted ER < 0.30, CYP450 IC50s > 25 5M, oral BA > 30%). To address this overarching objective, we propose the following three specific aims: Specific Aim 1: To synthesize and characterize a focused and structurally diverse library of synthetic peroxides. Specific Aim 2: To assess trematocidal activity and selectivity of target synthetic peroxides against two major human food-borne trematode species, Fasciola hepatica and Clonorchis sinensis. Specific Aim 3: To determine metabolism and pharmacokinetic parameters and initiate mechanism of action studies for selected synthetic peroxides. PUBLIC HEALTH RELEVANCE Food-borne trematodiases, caused by infection with liver flukes, affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of these diseases, new drugs are urgently needed. Praziquantel and triclabendazole are the only drugs now available and the development of resistance cannot be ignored, particularly in view of the large-scale use of praziquantel in many endemic countries. In this proposal, we propose to identify a new broad-spectrum orally-active trematocidal drug development candidate.

描述(申请人提供)：食源性吸虫病影响数亿人，特别是发展中国家的农村贫困人口。由于目前无法获得疫苗，而且不太可能在短期内提供预防食源性吸虫病的疫苗，因此有效的药物是控制发病率的唯一实用手段。重要的是，迫切需要治疗这些疾病的新药，因为吡喹酮和三氯苯达唑是唯一可用的药物，抗药性的发展不能被忽视，特别是考虑到吡喹酮在许多流行国家的大规模使用。这个项目的根本是我们的发现，几种合成的过氧化氢也具有很强的杀吸虫活性。我们建议进一步探索合成的过氧物作为新型杀吸虫药物的潜力。确定一种新的、广谱的、具有口服活性的合成过氧化氢杀吸虫药物开发候选药物将把耐药性降至最低，并为食源性吸虫酶带来更好的治疗和控制选择。新药开发候选药物的基本特征包括经济可行和可扩展的合成，良好的口服活性，低毒性和抗药性发展的潜力，广泛的杀吸虫活性，以及对脊椎动物宿主中所有寄生虫阶段的高效。更具体地说，我们的目标是确定一种候选药物，在剂量为100 mg/kg的情况下，对肝片吸虫幼虫和成虫和中华绒毛虫具有100%的减虫率，并具有良好的ADME谱(预测ER&lt；0.30，CYP450 IC50s&gt；25.M，口服BA&gt；30%)。为了解决这一首要目标，我们提出了以下三个具体目标：具体目标1：合成和表征一个具有焦点和结构多样性的合成过氧化物库。具体目的2：评价目标合成的过氧化物对两种主要的人类食源性吸虫物种肝片吸虫和华支睾吸虫的杀吸虫活性和选择性。具体目标3：测定选定的合成过氧物的代谢和药代动力学参数，并启动作用机制研究。公共卫生相关性由肝吸虫感染引起的食源性吸虫病影响着数亿人，特别是发展中国家的农村贫困人口。由于目前无法获得疫苗，而且不太可能在短期内提供预防这些疾病的疫苗，因此迫切需要新的药物。吡喹酮和三氯苯达唑是目前唯一可用的药物，抗药性的发展不能被忽视，特别是考虑到吡喹酮在许多流行国家的大规模使用。在这项提案中，我们建议确定一种新的广谱口服活性杀吸虫药物开发候选药物。

项目成果

Activity of OZ78 analogues against Fasciola hepatica and Echinostoma caproni.

• DOI: 10.1016/j.actatropica.2011.02.003
• 发表时间: 2011-04
• 期刊: ACTA TROPICA
• 影响因子: 2.7
• 作者: Kirchhofer, Carla;Vargas, Mireille;Braissant, Olivier;Dong, Yuxiang;Wang, Xiaofang;Vennerstrom, Jonathan L.;Keiser, Jennifer
• 通讯作者: Keiser, Jennifer

Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.

• DOI: 10.1021/jm100226t
• 发表时间: 2010-05-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhao Q;Vargas M;Dong Y;Zhou L;Wang X;Sriraghavan K;Keiser J;Vennerstrom JL
• 通讯作者: Vennerstrom JL

Tetrasubstituted pyrazinones derived from the reaction of praziquantel with N-bromosuccinimide.

由吡喹酮与N-溴代琥珀酰亚胺反应衍生的四取代吡嗪酮。

• DOI: 10.1016/j.tetlet.2014.06.083
• 发表时间: 2014
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Zhao,Qingjie;Wang,Chunkai;Ezell,EdwardL;Dong,Yuxiang;Vennerstrom,JonathanL
• 通讯作者: Vennerstrom,JonathanL

The activity of dispiro peroxides against Fasciola hepatica.

二螺过氧化物对肝片形吸虫的活性。

• DOI: 10.1016/j.bmcl.2011.07.024
• 发表时间: 2011
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Wang,Xiaofang;Zhao,Qingjie;Vargas,Mireille;Dong,Yuxiang;Sriraghavan,Kamaraj;Keiser,Jennifer;Vennerstrom,JonathanL
• 通讯作者: Vennerstrom,JonathanL